Genetic engineering techniques to excise a target nucleic acid from a host cell genome or an episome are needed in a variety of fields including metabolic engineering, industrial microbiology, synthetic biology, and basic molecular genetics research. Previous methods for removal of target nucleic acids, however, have been restricted and limited in application. Site specific recombinase methods of removal, for example, leave behind deleterious specific recombinase binding sites that create potential genomic instabilities within the host cells. Other methods can produce excision events at low frequency, thus necessitating methods for growth-selection of rare host cells that undergo the excision event. There exists a need for nucleic acids, compositions, and methods that can allow for high frequency and high fidelity excision of a target nucleic acid from a host cell genome or an episome without creating potential genomic instabilities.